Drugs ride the wave across tissue barriers

Macromolecular drugs traveling through the gastrointestinal tract are met by hard-to-breach tissue barriers that limit uptake and, in turn, dilute or prevent the drugs’ effects. Schoellhammer and colleagues repurposed a common technology in the clinic (ultrasound) to temporarily disrupt structural and physiological tissue barriers, allowing drugs to pass through. The initial application of a handheld ultrasonic probe was for rectal delivery of drugs, with a focus on treating a form of inflammatory bowel disease (IBD), called ulcerative colitis (UC). Patients with UC have few efficacious therapies, but drug enemas seem to work the best, as long as the patient isn’t suffering from diarrhea and the drug is absorbed quickly. The authors found that ultrasonic waves drove insulin and mesalamine into pig colonic tissue faster than natural absorption, without any physical or thermal damage to tissue. Ultrasound was also instrumental in encouraging mesalamine into mouse colonic tissues, leading to the resolution of acute colitis. Ultrasound-mediated drug delivery could be used for other drugs, such as hydrocortisone, and even macromolecules, such as insulin, as demonstrated by the authors, thus serving as a simple physical solution to the barrier challenge in gastrointestinal drug delivery.

Abstract

There is a significant clinical need for rapid and efficient delivery of drugs directly to the site of diseased tissues for the treatment of gastrointestinal (GI) pathologies, in particular, Crohn’s and ulcerative colitis. However, complex therapeutic molecules cannot easily be delivered through the GI tract because of physiologic and structural barriers. We report the use of ultrasound as a modality for enhanced drug delivery to the GI tract, with an emphasis on rectal delivery. Ultrasound increased the absorption of model therapeutics inulin, hydrocortisone, and mesalamine two- to tenfold in ex vivo tissue, depending on location in the GI tract. In pigs, ultrasound induced transient cavitation with negligible heating, leading to an order of magnitude enhancement in the delivery of mesalamine, as well as successful systemic delivery of a macromolecule, insulin, with the expected hypoglycemic response. In a rodent model of chemically induced acute colitis, the addition of ultrasound to a daily mesalamine enema (compared to enema alone) resulted in superior clinical and histological scores of disease activity. In both animal models, ultrasound treatment was well tolerated and resulted in minimal tissue disruption, and in mice, there was no significant effect on histology, fecal score, or tissue inflammatory cytokine levels. The use of ultrasound to enhance GI drug delivery is safe in animals and could augment the efficacy of GI therapies and broaden the scope of agents that could be delivered locally and systemically through the GI tract for chronic conditions such as inflammatory bowel disease.